Molecular mechanism by which residues at position 481 and 546 of measles virus hemagglutinin protein define CD46 receptor binding using a molecular docking approach.

The hemagglutinin (H) protein of measles viruses (MeV) mediates binding to the cellular receptors, CD46,human signaling lymphocyte activation molecule and nectin-4. Vaccine strains primarily contain H-proteins possessing MeV-H: Y481 and can utilize CD46. Reports suggest that a single amino acid change in MeV-H at position 481 in wild type strains renders them inefficient in utilizing CD46. The in-depth molecular mechanism by which substitutions at 481 and another reported critical residue position 546 affects CD46 binding affinity however remains elusive. We used molecular docking studies of CD46 with MeV-H possessing Y481 N/D to understand the in-depth molecular mechanism involved. It was found that loss in either of the hydrogen bond (H-bond) contacts (MeV-H:481-CD46:65, MeV-H:546-CD46:63) in the central contact region prevented efficient CD46 binding. Y481 N could form the specific H-bond, while G546S H-bond could be formed only in conjunction with Y481, revealing the significance of these residues in determining CD46 receptor binding potential. Elucidating the underlying molecular mechanism of receptor usage by the MeV has implications to understanding cellular tropism, viral pathogenesis and therapy.